PROJECT ABSTRACT The peripheral and central elements of the respiratory control system are not ?fixed,? but undergo sustained (neuroplastic) circuit reorganization to optimize function. This system can selectively utilize unique afferent modalities and brainstem neural pathways to elicit episodic, coordinated airway protective behaviors (e.g. cough, laryngeal adduction). Neuroplasticity is induced and undermined by inflammation, transient afferent feedback, or CNS injury. As a result, breathing responses and airway protective behaviors are altered in ways that can be adaptive or maladaptive. Existing models of the brainstem network and sensory control system regulating breathing and airway protection do not explain changes in responses caused by neuroplasticity in sensory, central integrating and efferent motor elements of the control system. This knowledge gap concerning peripheral and central circuit-based processes increases the risk of inappropriate depression in breathing or airway protective mechanisms by the neuromodulatory approaches being investigated in the SPARC initiative. In this project, our goal is to understand fundamental principles of modulation and plasticity in afferent pathways, brain networks and efferent systems controlling breathing and airway defense. The proposed research will advance our understanding of circuits underlying respiratory control, laying the foundation for future neuromodulatory strategies to normalize lung function in vulnerable clinical populations. We have assembled a multidisciplinary team to utilize cutting edge genetic, neuroanatomical, neurophysiological and computational modeling approaches to interrogate sensory, central and motor pathways of the respiratory control system. Complementary studies will be performed in human patient populations with various forms of sensory or motor dysfunction, including those with laryngectomy, double lung transplants and unilateral vocal fold paralysis. Through these parallel studies, we will reveal fundamental mechanisms of respiratory neuroplasticity resulting from injury, disease and/or afferent activation. New knowledge from peripheral and central circuits in animal models and humans with pathologies will be used to create an iterative, computational neuromechanical model that incorporates key elements of neuroplasticity. This model will enable predictions as we develop neuromodulatory approaches to inform novel treatments for respiratory dysfunction. The project is separated into four encompassing aims. Aim 1: Identify neuroanatomical and functional plasticity of lung sensory mechanisms that regulate brainstem pathways for airway protective reflexes. Aim 2: Identify short time-scale and sustained, circuit-based plasticity in airway motor, brainstem and spinal respiratory motor pathways induced by sensory feedback (airway and diaphragm) and/or injury/disease. Aim 3: Investigate key features of neuroplasticity in human respiratory behaviors. Aim 4: Develop a neuromechanical computational model of the neural system controlling breathing and airway defense that incorporates plasticity induced by sensory afferent feedback and injury/disease.